Study pinpoints key mechanism in brain development, raising question about use of antiseizure drug

Oct 08, 2009

Researchers at the Stanford University School of Medicine have identified a key molecular player in guiding the formation of synapses — the all-important connections between nerve cells — in the brain. This discovery, based on experiments in cell culture and in mice, could advance scientists' understanding of how young children's brains develop as well as point to new approaches toward countering brain disorders in adults.

The new work also pinpoints, for the first time, the biochemical mechanism by which the widely prescribed drug gabapentin (also marketed under the trade name Neurontin) works. "We have solved the longstanding mystery of how this blockbuster drug acts," said Ben Barres, MD, PhD, professor and chair of neurobiology. The study shows that gabapentin halts the formation of new synapses, possibly explaining its therapeutic value in mitigating epileptic seizures and chronic pain. This insight, however, may lead physicians to reconsider the circumstances in which the drug should be prescribed to pregnant women.

The paper, to be published online Oct. 8 in the journal Cell, looks at the interaction between neurons — the extensively researched that account for 10 percent of the cells in the brain — and the less-studied but much more common called astrocytes. Much work has been done on how neurons transmit electrical signals to each other through synapses — the nanoscale electrochemical contact points between neurons. It is the brain's circuitry of some 100 trillion of these synapses that allow us to think, feel, remember and move.

It is commonly agreed that the precise placement and strength of each person's trillions of synaptic connections closely maps with that person's cognitive, emotional and behavioral makeup. But exactly why a particular synapse is formed in a certain place at a certain time has largely remained a mystery. In 2005, Barres took a big step toward explaining this process when he and his colleagues discovered that a protein astrocytes secrete, called thrombospondin, is essential to the formation of this complex brain circuitry.

Still, no one knew the precise mechanism by which thrombospondin induced synapse formation.

In this new study, Barres, lead author Cagla Eroglu, PhD, and their colleagues demonstrate how thrombospondin binds to a receptor found on neurons' outer membranes. The role of this receptor, known as alpha2delta-1, had been obscure until now. But in an experiment with mice, the scientists found that neurons lacking alpha2delta-1 were unable to form synapses in response to thrombospondin stimulation.

And when the researchers grew neurons in a dish that were bioengineered to overexpress this receptor, those neurons produced twice as many synapses in response to stimulation with thrombospondin than did their ummodified counterparts.

The new discovery about alpha2delta-1's key role in synapse formation carries important implications for understanding the cause of pain and of epilepsy and developing improved medications for these conditions.

It was already known that alpha2delta-1 is the neuronal receptor for gabapentin, one of the world's most widely administered medications. Gabapentin is often prescribed for epilepsy and chronic pain, and its off-label use for other indications is widespread. Up to now, the molecular mechanism of gabapentin's action — what, exactly, it's doing to counter seizures or chronic pain — was unknown. But both syndromes may involve excessive numbers of synaptic connections in local areas of the brain.

In their new study, Barres and his colleagues found that when gabapentin was administered in developing mice, it bound to alpha2delta-1, preventing thrombospondin from binding to the receptor and, in turn, impeding synapse formation. Likewise, by blocking thrombosponin, gabapentin may reduce excess synapse formation in vulnerable areas of the human brain.

Barres noted that he and his colleagues found that gabapentin does not dissolve pre-existing synapses, but only prevents formation of new ones. That greatly diminishes gabapentin's potential danger to adults. In mature human brains, astrocytes ordinarily produce very little thrombospondin, and adult neurons don't form many new synapses, although some new synapses do continue to be formed throughout life — for example, in a part of the brain where new memories are laid down and at sites of injury to neurons, such as occurs after a stroke.

But the new findings raise questions about gabapentin's effect in situations where synapse formation is widespread and crucial, most notably in pregnancies. The vast bulk of the brain's synapses are formed during gestation and the very early months and years after birth. Because gabapentin easily crosses the placental barrier, it could potentially interfere with a fetus' rapidly developing brain just when global synapse formation is proceeding at breakneck speed.

"It's a bit scary that a drug that can so powerfully block synapse formation is being used in pregnant women," Barres said. "This potential effect on fetal brains needs to be taken seriously. Right now, doctors have the view that gabapentin is the safest anticonvulsant. There is no question that pregnant women with epilepsy who have been advised by their neurologists to continue their anticonvulsant treatment with gabapentin during their pregnancy should definitely remain on this drug until instructed otherwise. But there is no long-term registry being kept to track gabapentin-exposed babies. Our findings are saying that we need to be following up on these newborns so that their cognitive performance can be studied as they grow older."

Source: Stanford University Medical Center (news : web)

Explore further: Safe driving period calculated following first-time seizure

add to favorites email to friend print save as pdf

Related Stories

Immune system may target some brain synapses

Dec 13, 2007

A baby's brain has a lot of work to do, growing more neurons and connections. Later, a growing child's brain begins to pare down these connections until it develops into the streamlined brain of an adult.

Scientists find seizure drug reverses cellular effects

May 28, 2008

In the new research, published in the May 28, 2008 edition of The Journal of Neuroscience, the scientists found that gabapentin normalizes the action of certain brain cells altered by chronic alcohol abuse in an area of the ...

New study reveals brain cell mechanism of alcohol dependence

May 28, 2008

A study released today reveals a cellular mechanism involved in alcohol dependence. The study, in the May 28 issue of The Journal of Neuroscience, shows that gabapentin, a drug used to treat chronic pain and epilepsy, reduce ...

Scientists identify machinery that helps make memories

Oct 30, 2008

A major puzzle for neurobiologists is how the brain can modify one microscopic connection, or synapse, at a time in a brain cell and not affect the thousands of other connections nearby. Plasticity, the ability of the brain ...

Researchers visualize formation of a new synapse

Jun 18, 2009

A protein called neuroligin that is implicated in some forms of autism is critical to the construction of a working synapse, locking neurons together like "molecular Velcro," a study lead by a team of UC Davis researchers ...

SUMO wrestling in the brain

May 07, 2007

Increasing the amount of SUMO, a small protein in the brain, could be a way of treating diseases such as epilepsy and schizophrenia, reveal scientists at the University of Bristol, UK. Their findings are published online ...

Recommended for you

Children with autism have extra synapses in brain

8 hours ago

Children and adolescents with autism have a surplus of synapses in the brain, and this excess is due to a slowdown in a normal brain "pruning" process during development, according to a study by neuroscientists ...

Learning to play the piano? Sleep on it!

10 hours ago

According to researchers at the University of Montreal, the regions of the brain below the cortex play an important role as we train our bodies' movements and, critically, they interact more effectively after ...

User comments : 1

Adjust slider to filter visible comments by rank

Display comments: newest first

kuro
5 / 5 (1) Oct 08, 2009
It is also good to see that pharmaceutical companies who peddle various kinds of junk at obscene prices work by trial-and-error and have really, really no idea what their medicine actually does to people.